Cgrp receptor antagonist compounds for topical treatment of skin disorders

Abstract

The use of a CGRP receptor antagonist compound of formula (I) for topical application is described for treating and / or preventing skin inflammatory pathologies with a neurogenic component. More specifically, use of a CGRP receptor antagonist compound of formula (I) is described for topical application for treating and / or preventing rosacea, especially type I rosacea, atopic dermatitis, psoriasis and / or acne.

Description

[0001]The present invention relates to the use of CGRP receptor antagonist compounds and the pharmaceutical compositions comprising such compounds in dermatological field.BACKGROUND OF THE INVENTION[0002]CGRP (Calcitonin gene-related peptide) is broadly expressed in the central and peripheral nervous system and is involved in various biological functions. There are more and more evidence that CGRP play a key role as neuromodulator, but it is mostly known as a strong vasodilatator. CGRP activates a heterodimer receptor (CGRP-R) composed of a class B protein-G coupled receptor (CLR or calcitonin-like receptor)) associated with a transmembrane protein modifying the receptor activity (RAMP1 or receptor activity-modifying protein 1). Many studies have been done on CGRP role and CGRP receptor activity. For instance, studies have demonstrated that migraine attack was associated to the release of CGRP by meningeal nociceptors of the trigeminal ganglion and that CGRP could play a key role in...

AI Technical Summary

Benefits of technology

[0028]The invention provides a safe treatment to discontinue or decrease skin inflammation, especially linked to a neurogenic inflammation. The invention provides a long-term effect with limited toxic effects especially regarding hepatotoxicity.

[0029]Applicant surprisingly demonstrated that compounds of formula (I), well known for their high activity as CGRP antagonist compounds by oral route but also for their hepatic toxic effects, were highly effective as CGRP antagonists by topical application besides avoiding their well-known side effects. More specifically it has been demonstrated that the topical application of these CGRP antagonist compounds is effective for treating and / or preventing skin inflammatory pathologies especially linked to a neurogenic component such as rosacea, atopic dermatitis, psoriasis and / or acne.

Problems solved by technology

However their development was discontinued since severe hepatotoxicity was associated to these compounds by oral route.

These skin disorders are common but their diagnosis can be difficult.

Indeed, the skin immune system have limited way to respond to internal and external stimuli and many diseases present an inflammatory profile with few distinctive characteristics.

The pathogenesis of rosacea is complex and not yet completely understood.

However these treatments do not allow treating and / or preventing efficiently all the symptoms associated with rosacea, especially, the neurogenic component such as the skin hyperreactivity and redness.

However, the conventional treating agents for atopic dermatitis using steroid and anti-histamine agents can only temporarily relieve symptoms.

In addition, when topical or oral steroids are administered for a long term, the skin of a patient wears thin and osteoporosis is induced.

However, this drug is suspected of carrying a cancer risk and FDA (Food Drug Administration) has even issued a health warning in March 2005.

The current available treatments permit mostly to control the symptoms with a limited efficacy and may be use only during short time periods.

However these treatments are not really efficient and generate several side effects when used during a long time period such as skin irritations and a pathology aggravation after treatment interruption.

However, these available therapies are harsh on the skin and can cause dryness, irritation, or redness.

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